Growth factors, including members of the FGF and Wnt families, are pleiotropic regulators of proliferation, differentiation, migration, and survival in a variety of cell types. For example, basic fibroblast growth factor (bFGF or FGF-2) has been used to influence cellular growth, differentiation and migration (Bikfalvi et al., Endocrine Rev. 18:26-45, 1997; Friesel et al., FASEB J. 9:919-925, 1995; Moyamoto et al., J. Cell. Physiol. 177:58-67, 1998; D'Amore et al., Growth Factors 8:61-75, 1993) and is also a potent stimulator of angiogenesis (Moyamoto et al., J. Cell. Physiol. 177:58-67, 1998; D'Amore et al., Growth Factors 8:61-75, 1993) and hematopoiesis in vivo (Allouche et al., Prog. Growth Factor 6:35-48, 1995). FGF-2 is involved in organogenesis (Martin, Genes Dev. 12:1571-1586, 1998), vascularization (D'Amore et al., Growth Factors 8:61-75, 1993), and wound healing (Ortega et al., Proc. Natl. Acad. Sci. USA, 95:5672-5677, 1998), and plays an important role in the differentiation and/or function of various organs, including the nervous system (Ortega et al., Proc. Natl. Acad. Sci. USA, 95:5672-5677, 1998), the skeleton (Montero et al., J. Clin. Invest. 105:1085-1093, 2000), and several other organs (Bikfalvi et al., Endocrine Rev. 18:26-45, 1997). Because of its angiogenic and anabolic properties, FGF-2 has received considerable attention for potential clinical applications, including wound healing and tissue repair.
The therapeutic utility of the FGF-2 protein therapy has been assessed in various animal models with promising results. Accordingly, administration of recombinant human FGF-2 protein improved the healing of ischemic wounds in rats (Quirinia et al., J. Plast. Reconstr. Surg. Hand Surg. 32:9-18, 1998), promoted scar-less healing of skin incisional wounds in normal rats (Akasaka et al., J. Pathol., 203:710-720, 2004; Spyrou et al., Br. J. Plast. Surg. 55:275-282, 2002), enhanced wound healing in healing-impaired diabetic rats (Takeuchi et al., J. Pharmacol. Exp. Ther. 281:200-207, 1997), and accelerated the wound healing of chick embryo chorioallantoic membrane (Ribatti et al., Angiogenesis 3:89-95, 1999). Administration of human recombinant FGF-2 protein also promoted fracture healing in the monkey (Kawaguchi et al., J. Clin. Endorinol. Metab. 86:875-880, 2001), improved cartilage repair in the rabbit (Tanaka et al., Tissue Engineering 10:633-641, 2004), stimulated early stages of tendon healing in the rat (Chan et al., Acta Orthop. Scand. 71:513-518, 2000), and led to formation of new trabeculae that physically connect with pre-existing trabeculae in osteopenic rats (Lane et al., J. Bone Miner Res. 18:2105-2115, 2003; Lane et al., Osteoporos Int. 14:374-382, 2003). Subcutaneous implantation of controlled-release FGF-2 protein into the back of mice resulted in de novo formation of adipose tissue (Tabata et al., Tissue Engineering 6:279-289, 2000).
Nonetheless, attempts to use FGF-2 in gene transfer approaches have led to inconsistent results. While ex vivo FGF-2 promoted collateral vessel development in a rabbit hind limb ischemia model (Ishii et al., J. Vasc. Surg. 39:629-638, 2004) and improved blood flow and cardiac function in a swine myocardial ischemia model (Ninomiya et al., Gene Ther. 10:1152-1160, 2003), in vivo expression of FGF-2 from a plasmid vector did not significantly improve survival of rat ischemic myocutaneous flaps (Hijjawi et al., Arch. Surg. 139:142-147, 2004). Similarly, the in vivo FGF-2 expression failed to preserve functional responses to photoreceptor in a rat retinal degeneration model (Spencer et al., Mol. Ther. 3:746-756, 2001).
Thus, there exists a need for compositions and methods for increasing the efficacy of treatment using osteogenic growth factors, such as FGF-2, to enhance bone growth and repair for the treatment of a wide variety of skeletal disorders. The compositions and methods disclosed herein address this need, providing numerous benefits, which will become apparent upon review of the specification.